The locus coeruleus (LC) serves as a nexus for the integration of arousal, memory, autonomic function and stress. It is also an important site for the modulation of acute nociception by opioids. Comparatively little is known about the function of the LC during persistent pain or how persistent pain states may alter the responses of LC neurons. Preliminary data indicate that the efficacy of DAMGO, a selective mu opioid receptor (MOR) agonist, is greatly reduced in the LC of rats with sustained inflammation produced by injection of complete Freund's adjuvant (CFA) in the hindpaw. We hypothesize that persistent pain states may induce (1) a sustained release of endogenous opioid peptides in the LC that causes a compensatory desensitization or downregulation of MORs and (2) phosphorylation of tyrosine residues in MORs that may decrease agonist efficacy or cause receptor downregulation. Opioid receptor antagonists will be microinjected in the LC of CFA- or saline-treated rats to determine whether they produce or exacerbate thermal hyperalgesia, indicative of an increased release of endogenous opioid agonist. Levels of these peptides in the LC of saline- and CFAtreated rats will be determined by RIA and ELISA. Radioligand binding studies will determine the Kd and Bmax for MORs in homogenates of LC from saline and CFA-treated rats. Finally, whole-cell voltage clamp recordings of LC neurons will determine how inhibition of protein tyrosine phosphatases and kinases alters the effects of DAMGO in saline- and CFA-treated rats. These studies will provide new insights into how persistent pain states alter the actions of opioid analgesics, as well as the adaptive changes that occur supraspinally under conditions of persistent pain. They may also provide new insights into the mechanisms that underlie endogenous opioid tolerance and dependence.